(±)-4-Amino-3-(4-chlorophenyl)butanoic acid (baclofen), (1), is an analog of gamma-aminobutyric acid (i.e., GABA) that selectively activates GABAB receptors, resulting in neuronal hyperpolarization. GABAB receptors are located in laminae I-IV of the spinal cord, where primary sensory fibers end. These G-protein coupled receptors activate conductance by K+-selective ion channels and may reduce currents mediated by Ca2+ channels in certain neurons. Baclofen has a presynaptic inhibitory effect on the release of excitatory neurotransmitters and also acts postsynaptically to decrease motor neuron firing (see Bowery, Trends Pharmacol. Sci. 1989, 10, 401-407; Misgeld et al., Prog. Neurobiol. 1995, 46, 423-462).

Many examples of compounds having antagonistic activity at GABAB receptors exist and block the effects of baclofen in vitro and in vivo. Examples of GABAB antagonists include certain aminophosphonic acids (e.g. phaclofen), aminosulfonic acids (e.g. saclofen and 2-hydroxysaclofen), and aminophosphinic acids, particularly certain 3-aminopropylphosphinic acids.
Certain 3-aminopropylphosphinic acid analog GABAB antagonists are described in Froestl et al., J. Med. Chem. 1995, 38, 3313-3331; Dingwall et al., Tetrahedron 1989, 45, 3787-3808; Deprele and Montchamp, J. Org. Chem. 2001, 66, 6745-6755; Dingwall et al., U.S. Pat. No. 4,656,298; Baylis et al., U.S. Pat. No. 5,013,863; Baylis et al., U.S. Pat. No. 5,051,524; Baylis et al., U.S. Pat. No. 5,300,679; Marescaux et al., U.S. Pat. No. 5,229,379; Marescaux et al., U.S. Pat. No. 5,407,922; Mickel et al., U.S. Pat. No. 5,332,729; Mickel, U.S. Pat. No. 5,376,684; and Mickel et al., U.S. Pat. No. 5,424,441. Examples of aminopropylphosphinic analog GABAB antagonists include:    3-Aminopropyl(n-butyl)phosphinic acid;    3-Aminopropyl(diethoxymethyl)phosphinic acid;    3-Aminopropyl(benzyl)phosphinic acid;    3-Amino-2(S)-hydroxypropyl(benzyl)phosphinic acid;    3-Amino-2-hydroxypropyl(cyclohexylmethyl)phosphinic acid;    3-Amino-2(S)-hydroxypropyl(cyclohexylmethyl)phosphinic acid;    3-(4-Chlorobenzylamino)-2(R)-hydroxypropyl(benzyl)phosphinic acid;    3-(4-Chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid;    3-(4-Chlorobenzylamino)-2-hydroxypropyl(n-butyl)phosphinic acid;    3-(3,4-Dichlorobenzylamino)-2(S)-hydroxypropyl(benzyl)phosphinic acid;    3-(3,4-Dichlorobenzylamino)-2(S)-hydroxypropyl(diethoxymethyl)phosphinic acid;    3-(4-Chlorobenzylamino)propyl(cyclohexylmethyl)phosphinic acid;    3-{N-[1-(3,4-Dichlorophenyl)ethyl]amino}-2-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1-(3,4-Dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1-(3,4-Dichlorophenyl)ethyl]amino}-2(R)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1 (R)-(3,4-Dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1(S)-(3,4-Dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1 (R)-(3,4-Dichlorophenyl)ethyl]amino}-2(R)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1(S)-(3,4-Dichlorophenyl)ethyl]amino}-2(R)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1-(3,4-Dichlorophenyl)ethyl]amino}-2-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1-(3,4-Dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1-(3,4-Dichlorophenyl)ethyl]amino}-2(R)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1 (R)-(3,4-Dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1(S)-(3,4-Dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1(R)-(3,4-Dichlorophenyl)ethyl]amino}-2(R)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1(S)-(3,4-Dichlorophenyl)ethyl]amino}-2(R)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1-(3-Carboxyphenyl)ethyl]amino}-2-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1-(3-Carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1-(3-Carboxyphenyl)ethyl]amino}-2(R)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1 (R)-(3-Carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1(S)-(3-Carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1 (R)-(3-Carboxyphenyl)ethyl]amino}-2(R)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1(S)-(3-carboxyphenyl)ethyl]amino}-2(R)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid;    3-{N-[1-(3-Carboxyphenyl)ethyl]amino}-2-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1-(3-Carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1-(3-Carboxyphenyl)ethyl]amino}-2(R)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1 (R)-(3-Carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1(S)-(3-Carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1 (R)-(3-Carboxyphenyl)ethyl]amino}-2(R)-hydroxy-propyl-(benzyl)-phosphinic acid;    3-{N-[1(S)-(3-Carboxyphenyl)ethyl]amino}-2(R)-hydroxy-propyl-(benzyl)-phosphinic acid;
pharmaceutically acceptable salts of any of the foregoing, and pharmaceutically acceptable solvates of any of the foregoing.
GABAB antagonists are useful in the treatment of cognitive or memory disorders including Mild Cognitive Impairment (MCI) and cognitive impairment associated with Alzheimer's disease (see e.g., Baylis et al., U.S. Pat. No. 5,190,933; Pearlman et al., U.S. Application Publication No. 2002/0187977; Froestl et al., Biochem. Pharmacol. 2004, 68, 1479-1487; Helm et al., Neuropharmacol. 2005, 48, 956-964; Mondadori et al., Behav. Brain Res. 1996, 77, 227-229; Mondadori et al., Behav. Neural Biol. 1993, 60, 62-68; and Nakagawa et al., Brain Res. 1997, 766, 101-106).
GABAB antagonists are also useful in the treatment of depressive moods or anxiety states (see e.g., Slattery et al., J. Pharmacol. Exp. Ther. 2005, 312, 290-296; and Nakagawa et al., Eur. J. Pharmacol. 1999, 381, 1-7).
GABAB antagonists are also useful in the treatment of epilepsy, particularly “petit-mal” type epilepsy, including spontaneous absence epilepsy and atypical absence epilepsy (see e.g., Marescaux et al., U.S. Pat. No. 5,407,922; Marescaux et al., U.S. Pat. No. 5,545,631; Czuczwar and Patsalos, CNS Drugs, 2001, 15, 339-350; Getova et al., Eur. J. Pharmacol. 1997, 320, 9-13; Vergnes et al., Eur. J. Pharmacol. 1997, 332, 245-255; and Marescaux et al., J. Neural Transm. 1992, 35, 179-188).
Typical ligands for GABAB receptors such as baclofen and the zwitterionic 3-aminopropylphosphinic acids noted above are polar molecules that lack the requisite physicochemical characteristics for effective passive permeability across cellular membranes. For baclofen, passage of the drug across the gastrointestinal (GI) tract and the blood-brain barrier (BBB) is mediated primarily by active transport processes rather than by passive diffusion. Accordingly, baclofen is a substrate for active transport mechanisms shared by neutral α-amino acids such as leucine and β-amino acids such as β-alanine and taurine (van Bree et al., Pharm. Res. 1988, 5, 369-371; Cercos-Fortea et al., Biopharm. Drug. Disp. 1995, 16, 563-577; Deguchi et al., Pharm. Res. 1995, 12, 1838-1844; Moll-Navarro et al., J. Pharm. Sci. 1996, 85, 1248-1254). 3-Aminopropylphosphinic acids are also likely to exploit related active transport mechanisms to permeate the GI mucosa following oral administration.
Another common feature shared by baclofen and 3-aminopropylphosphinic acid GABAB receptor antagonists is their rapid clearance from the systemic circulation, which leads to the necessity for frequent dosing in humans (e.g. three or four times daily) (see Bowery, supra; “Commercial and Pipeline Perspectives: Upper GI Disorders”, Data Monitor Report, September 2004, p. 147; Gleiter et al., J. Clin. Pharm. 1996, 36, 428-438; and Froestl et al., Biochem. Pharmacol. 2004, 68, 1479-1487). Sustained release oral dosage formulations are a conventional solution to the problem of rapid systemic drug clearance, as is well known in the art (see e.g., “Remington's Pharmaceutical Sciences,” Philadelphia College of Pharmacy and Science, 19th Edition, 1995). Osmotic delivery systems are also recognized methods for sustained drug delivery (see e.g., Verma et al., Drug Dev. Ind. Pharm. 2000, 26, 695-708). Successful application of these technologies depends on the drug of interest having an effective level of absorption from the large intestine (also referred to herein as the colon), where the dosage form spends a majority of its time during its passage down the gastrointestinal tract. Baclofen, and likely other zwitterionic GABAB receptor ligands, is poorly absorbed following administration into the colon in animal models (Merino et al., Biopharm. Drug. Disp. 1989, 10, 279-297), presumably because the transporter proteins mediating baclofen absorption in the upper region of the small intestine are not expressed in the large intestine. Development of an oral controlled release formulation for zwitterionic GABAB receptor antagonists should considerably improve the convenience, efficacy, and side effect profile of GABAB antagonist therapy. However, the rapid passage of conventional dosage forms through the proximal absorptive region of the small intestine has thus far prevented the successful application of sustained release technologies to these drugs. A number of exploratory delivery technologies that rely on either mucoadhesion or gastric retention have been suggested to achieve sustained delivery of baclofen (Sinnreich, U.S. Pat. No. 4,996,058; Khanna, U.S. Pat. No. 5,091,184; Fara et al., supra; Dudhara et al., International Publication No. WO 03/011255) though to date none of these appear to be able to achieve sustained blood levels of baclofen in human subjects. More recently, acyloxyalkyl carbamate prodrugs of baclofen and analogs thereof have been shown to provide enhanced bioavailability of baclofen following oral administration as described in co-pending application Gallop et al., International Publication No. WO 2005/019163 entitled “Acyloxyalkyl Carbamate Prodrugs, Methods, Synthesis and Use,” filed Aug. 20, 2004. Thus, there is a need for new prodrugs of 3-aminopropylphosphinic acid GABAB receptor antagonists, which are well absorbed in the large intestine/colon and hence are suitable for oral sustained release formulations, thus improving the convenience, efficacy, and side effect profile of GABAB antagonist therapy.